The Two Micron All Sky Survey (2MASS) Skrutskie, M. F; Cutri, R. M; Stiening, R ...
The Astronomical journal,
02/2006, Letnik:
131, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Between 1997 June and 2001 February the Two Micron All Sky Survey (2MASS) collected 25.4 Tbytes of raw imaging data covering 99.998% of the celestial sphere in the near-infrared J (1.25 mm), H (1.65 ...mm), and Ks (2.16 mm) bandpasses. Observations were conducted from two dedicated 1.3 m diameter telescopes located at Mount Hopkins, Arizona, and Cerro Tololo, Chile. The 7.8 s of integration time accumulated for each point on the sky and strict quality control yielded a 10 s point-source detection level of better than 15.8, 15.1, and 14.3 mag at the J, H, and Ks bands, respectively, for virtually the entire sky. Bright source extractions have 1 s photometric uncertainty of <0.03 mag and astrometric accuracy of order 100 mas. Calibration offsets between any two points in the sky are <0.02 mag. The 2MASS All-Sky Data Release includes 4.1 million compressed FITS images covering the entire sky, 471 million source extractions in a Point Source Catalog, and 1.6 million objects identified as extended in an Extended Source Catalog.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) ...protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and for at least nine months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.
A catalog is presented of IRAS observations of 85 galaxies with blue-light isophotal diameters greater than 8 arcmin. The observations, data processing, and data measurement techniques are described, ...and total IRAS flux densities and integrated infrared emission properties of the sample are reported. Infrared brightness profiles of the detected galaxies and infrared surface brightness contour maps of the galaxies for which structural features were resolved are displayed. A classification scheme based on the degree of central concentration and spatial structure of the 60 micron emission of the best-resolved galaxies is proposed. The 60 micron and blue-light isophotal diameters of the largest galaxies are compared.
Notch receptors and the amyloid precursor protein are type I membrane proteins that are proteolytically cleaved within their transmembrane domains by a presenilin (PS)-dependent γ-secretase activity. ...In both proteins, two peptide bonds are hydrolyzed: one near the inner leaflet and the other in the middle of the transmembrane domain. Under saturating conditions the substrates compete with each other for proteolysis, but not for binding to PS. At least some Alzheimer's disease-causing PS mutations reside in proteins possessing low catalytic activity. We demonstrate (i) that differentially tagged PS molecules coimmunoprecipitate, and (ii) that PS N-terminal fragment dimers exist by using a photoaffinity probe based on a transition state analog γ-secretase inhibitor. We propose that γ-secretase contains a PS dimer in its catalytic core, that binding of substrate is at a site separate from the active site, and that substrate is cleaved at the interface of two PS molecules.
Summary
Background
Mouse models of atopic march suggest that systemic, skin‐derived thymic stromal lymphopoietin (TSLP) mediates progression from eczema to asthma.
Objective
We investigated whether ...circulating TSLP is associated with eczema, allergic sensitization, or recurrent wheezing in young children.
Methods
A prospective analysis of the relationship between plasma levels of TSLP to allergic sensitization and recurrent wheezing was conducted in the birth cohort from the Urban Environment and Childhood Asthma (URECA) study. Plasma TSLP levels were measured at 1, 2, and 3 years of age and analysed for correlation with clinical parameters in each of the three years. Only those children with consecutive samples for all three years were included in this analysis.
Results
We detected TSLP in 33% of 236 children for whom plasma samples were available for all three years. Overall, a consistently significant association was not found between TSLP and eczema or allergic sensitization. With regard to recurrent wheezing, children with detectable TSLP at one year of age were significantly less likely to experience recurrent wheezing by 3 years compared with those children without detectable TSLP, but this was only seen in children without aeroallergen sensitization at 3 years (P < 0.01).
Conclusions and Clinical Relevance
Contrary to our expectations, circulating TSLP was not significantly associated with eczema, allergen sensitization, or recurrent wheezing during the first three years of life. Early presence of circulating TSLP was significantly associated with reduced incidence of recurrent wheeze in those children not sensitized to aeroallergen. These findings suggest a possible underlying distinction between pathogenesis of developing atopic vs. non‐atopic recurrent wheeze.
The Notch genes encode single-pass transmembrane receptors that transduce
the extracellular signals responsible for cell fate determination during several
steps of metazoan development. The mechanism ...by which extracellular signals
affect gene transcription and ultimately cell fate decisions is beginning
to emerge for the Notch signalling pathway. One paradigm is that ligand binding
to Notch triggers a Presenilin1-dependent proteolytic release of the Notch
intracellular domain from the membrane, resulting in low amounts
of Notch intracellular domain which form a nuclear complex with CBF1/Su(H)/Lag1
to activate transcription of downstream targets. Not all observations
clearly support this processing model, and the most rigorous test of it is
to block processing in vivo and then determine the ability of unprocessed
Notch to signal. Here we report that the phenotypes associated with a single
point mutation at the intramembranous processing site of Notch1, Val1,744→Gly,
resemble the null Notch1 phenotype. Our results show that
efficient intramembranous processing of Notch1 is indispensable for embryonic
viability and proper early embryonic development in vivo.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
8.
γ-Secretase Inhibitors Repress Thymocyte Development Hadland, Brandon K.; Manley, Nancy R.; Su, Dong-ming ...
Proceedings of the National Academy of Sciences - PNAS,
06/2001, Letnik:
98, Številka:
13
Journal Article
Recenzirano
Odprti dostop
A major therapeutic target in the search for a cure to the devastating Alzheimer's disease is γ-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of ...Aβ42 peptides, precipitates of which are thought to cause the disease. γ-Secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This has led to the hypothesis that therapeutic inhibition of γ-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Here, we show that application of γ-secretase inhibitors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8-state to an intermediate CD4+/CD8+double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+single-positive maturation but did not affect CD4+single-positive cells. These results demonstrate that pharmacological γ-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and present a system in which rapid evaluation of γ-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.
γ-secretase-like proteolysis at site 3 (S3), within the transmembrane domain, releases the
N
otch
i
ntra
c
ellular
d
omain (NICD) and activates CSL-mediated Notch signaling. S3 processing occurs only ...in response to ligand binding; however, the molecular basis of this regulation is unknown. Here we demonstrate that ligand binding facilitates cleavage at a novel site (S2), within the extracellular juxtamembrane region, which serves to release ectodomain repression of NICD production. Cleavage at S2 generates a transient intermediate peptide termed NEXT (
N
otch
ex
tracellular
t
runcation). NEXT accumulates when NICD production is blocked by point mutations or γ-secretase inhibitors or by loss of presenilin 1, and inhibition of NEXT eliminates NICD production. Our data demonstrate that S2 cleavage is a ligand-regulated step in the proteolytic cascade leading to Notch activation.
Human papillomavirus (HPV) types 16, 18, 31, and 33 have been implicated as etiologic agents of cervical and penile cancer. Using a cell culture system for keratinocytes which allows stratification ...and production of differentiation-specific keratins, we have examined the effects of one of these viruses, HPV-16, on the differentiation capabilities of human epithelial cells. A plasmid containing the HPV-16 genome and a neomycin-selectable marker was transfected into primary human epidermal cells and SCC-13 cells, an immortalized squamous cell carcinoma cell line. Cloned neomycin-resistant cell lines were isolated and examined by cell culture on raised collagen rafts. Cell lines containing HPV-16 DNA retained the ability to stratify and express differentiation-specific keratins in the raft system but otherwise failed to differentiate normally. The histological abnormalities induced by HPV-16 closely resembled those seen in genital intraepithelial neoplasia in vivo. Hence, our results support the role of HPV-16 as an etiologic agent in the development of genital neoplasias and suggest a specific system for the study of HPV-16-induced epithelial cancers.
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